Conformation-dependent antibacterial activity of the naturally occurring human peptide LL-37.
The influence of ion composition, pH, and peptide concentration on the conformation and activity of the 37-residue human antibacterial peptide LL-37 has been studied. At micromolar concentration in water, LL-37 exhibits a circular dichroism spectrum consistent with a disordered structure. The addition of 15 mM HCO3-, SO42-, or CF3CO2- causes the peptide to adopt a helical structure, with approximately equal efficiency, while 160 mM Cl- is less efficient. A cooperative transition from disordered to helical structure is observed as the peptide concentration is increased, consistent with formation of an oligomer. The extent of alpha-helicity correlates with the antibacterial activity of LL-37 against both Gram-positive and Gram-negative bacteria. Two homologous peptides, FF-33 and SK-29, containing 4 and 8 residue deletions at the N terminus, respectively, require higher concentrations of anions for helix formation and are less active than LL-37 against Escherichia coli D21. Below pH 5, the helical content of LL-37 gradually decreases, and at pH 2 it is entirely disordered. In contrast, the helical structure is retained at pH over 13. The minimal inhibitory concentration of LL-37 against E. coli is 5 microM, and at 13-25 microM the peptide is cytotoxic against several eukaryotic cells. In solutions containing the ion compositions of plasma, intracellular fluid, or interstitial fluid, LL-37 is helical, and hence it could pose a danger to human cells upon release. However, in the presence of human serum, the antibacterial and the cytotoxic activities of LL-37 are inhibited.
Johansson
J
J
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden.
Gudmundsson
G H
GH
Rottenberg
M E
ME
Berndt
K D
KD
Agerberth
B
B
D000818:Animals; D000838:Anions; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism*; D023181:Antimicrobial Cationic Peptides; D001770:Blood Bactericidal Activity; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D054804:Cathelicidins; D004926:Escherichia coli; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013552:Swine
D000838:Anions; D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D002352:Carrier Proteins; D054804:Cathelicidins